The antiplatelet agents prasugrel and clopidogrel both have useful properties and can play a critical role in reducing the risk of complications in acute coronary syndrome-a leading cause of morbidity and mortality
MRPharmS Clin Dip MSc
Basingstoke & North
Cardiovascular disease (CVD) is now the main cause of death in the UK. Coronary artery atherosclerosis is the main cause of coronary artery disease (CAD). Morbidity and mortality for such patients have been reduced by the introduction of coronary care units, angioplasty and national guidelines. The term acute coronary syndrome (ACS) covers both heart attacks for which emergency reperfusion therapy with thrombolytic drugs or primary angioplasty is used (ST elevation infarction STEMI) and those referred to as non-ST segment elevation myocardial infarction (NSTEMI) in whom different treatment is used. Many patients with ACS undergo percutaneous intervention (PCI). In 2007 national audit data revealed that over 77,000 PCI procedures were undertaken in the UK. Over 50% of these were for ACS management. Understanding the disease process and the process of atherosclerotic plaque rupture which leads to ACS has helped to target therapy. The rupture of vulnerable plaques releases a cascade of thrombogenic material to activate platelets, which can then propagate and occlude the affected artery. Much of the management of ACS is directed against platelet activity. Platelets play a major role in the pathogenesis of atherothrombosis and the formation of thrombi following PCI with or without stent placement. The use of antiplatelet agents in these procedures is essential to reduce the risk of complications such as a further myocardial infarction (MI), angina or stroke.
In the early 1990s early stent thrombosis occurred in approximately 10% of emergency PCI patients. This was associated with a high risk of death. At this time the combination of aspirin and warfarin was used to inhibit platelet activity. Ticlopidine was the first thienopyridine to be developed which inhibited platelet activity. It was significantly better at preventing stent thrombosis but at the risk of serious adverse effects such as neutropaenia, which required two-weekly monitoring of full blood counts, it was also poorly tolerated due to rashes or gastro-intestinal upset.
In 2000 the CLASSICS trial compared clopidogrel with ticlopidine, both in combination with aspirin. It concluded that clopidogrel had similar efficacy to ticlopidine, but was significantly safer, in terms of bleeding, reduced white cell counts and early drug discontinuation, 9.1% vs 4.5%, (p=0.005).4 After this, clopidogrel became standard therapy and ticlopidine was withdrawn from the UK market.
Clopidogrel is licensed for use in combination with aspirin for prevention of atherothrombotic events in patients with non-ST segment elevation ACS. It is also used for ST elevation MI (STEMI) in patients eligible for thrombolysis. Interestingly it is not licensed for prevention of stent thrombosis in elective procedures. Prasugrel is a relatively new antiplatelet agent indicated, in combination with aspirin, for prevention of atherothrombotic events (cardiovascular (CV) death, non-fatal MI or non-fatal stroke) in patients with ACS undergoing PCI.
Given the recent availability of generic clopidogrel within the UK and that the National Centre for Clinical Excellence (NICE) has recently issued guidance about the use of prasugrel, where do these two agents currently fit into clinical practice?
What are clopidogrel and prasugrel?
Both clopidogrel and prasugrel are thienopyridines that irreversibly inhibit adenosine phosphate (ADP)- induced platelet aggregation by preventing the binding of ADP to the P2Y12 receptor on the platelet. Both drugs are pro-drugs requiring further metabolism to be converted to their active forms. Clopidogrel is extensively metabolised by two cytochrome P450-dependent steps, whereas prasugrel is converted to active metabolite in a single step. Prasugrel is rapidly absorbed with concentrations peaking about 30 minutes after dosing. Clopidogrel is absorbed within 45 minutes; however, this can be variable with only about 50% absorbed.
Concerns have been raised about inter-individual variability of platelet inhibition with clopidogrel and the potential risk of further atherothrombotic events. It is believed that this may be due to its metabolism and genetic differences in cytochrome P450, in particular, isoforms of CYP2C19.
What evidence is there of benefit?
Evidence for the effects of clopidogrel in ACS comes from the CURE study. Clopidogrel and aspirin were compared with placebo and aspirin in 12,562 patients. Patients were eligible for the study if they presented within 24 hours of symptoms of ACS without ST segment elevation.
Patients were given a 300mg loading dose of clopidogrel followed by 75mg daily.
Over a period of nine months 9.3% of clopidogrel patients reached the endpoint of CV death, non-fatal MI or stroke, versus 11.4% on placebo, p = 0.009. The absolute risk reduction (ARR) was 2.1% with a number needed to treat (NNT) of 48. The difference was apparent after 30 days and was maintained over the study period. Unfortunately, major and minor bleeding were significantly more common in the clopidogrel group than with placebo (3.7% and 2.7%, respectively) and the number needed to harm (NNH) was 100. So, for every 100 patients treated with clopidogrel two MIs would be prevented at the expense of one major bleed. However, from this study NICE based its guidance on the use of clopidogrel in ACS.
For patients with STEMI the evidence for the effects of clopidogrel comes from CLARITY and COMMIT and more recently CURRENT-OASIS-7. This study was presented recently and looked at just over 25,000 patients with ACS or MI who were scheduled to undergo angiography within 72 hours. These patients were randomised to receive high-dose clopidogrel with a 600mg loading dose, then 150mg daily for a week, then 75mg daily, or the standard regimen of 300mg followed by 75mg daily.
At 30 days the combined risk of CV death, MI or stroke occurred in 4.4% of patients on the standard dose and in 4.2% of those on the high dose, but this is not a statistically significant difference. However, a third of patients had a normal angiogram which may explain the lack of difference. Of those that underwent PCI their risk of stent thrombosis was reduced by over 30% and their risk of MI reduced by 22% although this was at a cost of increased bleeding. So for every 1000 patients doubling the dose of clopidogrel will prevent six MIs and seven stent thromboses but three will have a severe bleed.
The Triton TIMI 38 study14 compared prasugrel and aspirin to clopidogrel and aspirin in 13,608 moderately high-risk ACS patients undergoing PCI. Patients received 60mg prasugrel loading dose followed by 10mg maintenance dose, or clopidogrel 300mg followed by 75mg. Patients were followed for up to 15 months.
Of those in the prasugrel group 9.9% experienced the primary endpoint of CV death, non-fatal MI or non-fatal stroke versus 12.1% in the clopidogrel group, p<0.001. This is an ARR of 2.2% and NNT of 45. Prasugrel did not demonstrate any mortality benefit. The main benefit was due to a reduction in MIs and not CV death or stroke. However, it is unclear how many symptomatic MIs were reduced as these were not distinguished from those MIs identified by biochemical markers only. This makes it more difficult to determine the effectiveness of prasugrel in comparison to clopidogrel.
Prasugrel was also associated with a significant increase in the risk of bleeding: 2.4% in those receiving prasugrel compared to 1.8% (p< 0.05) NNH 167. Three groups of patients were particularly at risk of major, life-threatening and fatal bleeding: those aged 75 years or older, those whose with weight under 60kg, and those who had a history of transient ischaemic attacks (TIA) or stroke. Consequently prasugrel is contra-indicated in patients with a history of TIAs or stroke and not recommended in people over the age of 75 years or people weighing less than 60kg, unless a lower, clinically unproven maintenance dose of 5mg is used.
Subgroup analysis of this study found that the reduction in the primary endpoint was greater in patients with diabetes mellitus (12.2% of prasugrel patients and 17% of clopidogrel, p< 0.001) than without diabetes mellitus (9.2% vs 10.6% p=0.02). The incidence of stent thrombosis, a rare but potential life-threatening condition, was also reduced in the prasugrel group, (1.1% vs 2.4% with clopidogrel). Subgroup analysis also looked at patients with ST-segment-elevation MI, STEMI.16 In this subgroup the primary endpoint was reached in 10% of the patients in the prasugrel group and in 12.4% in the clopidogrel group at 15 months, p=0.02. Patients undergoing primary PCI have a narrow window in which to receive optimal benefit and minimal damage to the myocardium — current guidelines recommend a door to balloon time of 90 minutes.17 A rapid onset of antiplatelet activity is essential. Prasugrel has a faster onset than clopidogrel and this is likely to be why this subgroup of patients benefited. However, concerns have been raised that patients were not pre-loaded with these antiplatelet agents (they were given up to one hour post-procedure) and this does not reflect current clinical practice. Clinical guidelines18 currently recommend that the loading dose is given immediately before and not after the procedure. In such circumstances a loading dose of 600mg clopidogrel would be used rather than a dose of 300mg. It is not known if the difference between prasugrel and a higher loading dose of clopidogrel would have reduced the difference between the two groups.
Use in clinical practice
When should prasugrel be used and where does it fit into current clinical practice? Clopidogrel has proven benefits but inter-patient variability in antiplatelet inhibition, ‘clopidogrel resistance’ and slow onset of activity remain valid concerns. Other concerns include the issues of gastro-protection. What is the clinical relevance of the interaction between clopidogrel and proton-pump inhibitors (PPIs)?; does concurrent omeprazole reduce the efficacy of clopidogrel? Current evidence does not justify these concerns, but until further data are available wide separation of the administration of these two drugs is recommended.19 Current guidance from the drug regulatory bodies in Europe (EMA) and the UK (MHRA) is to avoid concomitant use where possible.[20,21] Prasugrel, on the other hand, is not reported to interact with PPIs.
Across Europe generic clopidogrel is available. In the UK generic versions are based on the hydrochloride and the besilate salt, and are marketed for prevention of atherothrombotic events in patients suffering an MI, stroke or peripheral arterial disease but not for use in ACS. Plavix (clopidogrel hydrogen sulphate) is the marketed clopidogrel for use in those suffering from ACS. Concerns have been raised as to whether generic clopidogrel should be used ‘off label’ when there is a licensed product available.
Other concerns are whether different salts of the drug have similar efficacy to each other. It is possible that variability of clopidogrel activity is related to gastric acid and the pH of the stomach. This will affect the ionisation state of the salt and therefore its absorption.
Generic clopidogrel does have significant cost advantages over Plavix and even more over prasugrel. Prasugrel is 35% more expensive than clopidogrel.
NICE’s recent guidance recommends that prasugrel only be used when:
- immediate primary PCI for STEMI is necessary or
- stent thrombosis has occurred during clopidogrel treatment or
- the patient has diabetes mellitus.
Prior to this NICE guidance, many centres had developed their own guidelines for the use of prasugrel. Some were using prasugrel for patients at high risk of stent thrombosis based on the number of stents inserted, the length of stents, vessel type and other factors. NICE felt that this subgroup of patients was difficult to define and that there is no validated system to determine high risk patients. The balance of risk versus benefits in this group is uncertain and therefore they did not recommend its use in this patient population. The use of the 5mg dose is without any clinical evidence and in those patients where a 5mg dose would be indicated; under 60kg weight or over 75 years, some centres at present are using clopidogrel instead because it has the evidence base. Many centres will adopt the NICE guidance. However, many ambulance services and paramedics across the country have only just been enabled via recent guidance23 to administer clopidogrel. Thus those patients admitted via ambulance for whom primary PCI is appropriate are unlikely to receive prasugrel, unless the thienopyridine is withheld until the patient reaches the centre. The use of the 5mg dose of prasugrel is not supported by any clinical evidence and in those patients where a 5mg dose would be indicated – under 60kg weight or over 75 years – centres are currently using clopidogrel instead, on the basis of the available evidence.
In summary, clopidogrel will remain the first line therapy for most patients with ACS in the foreseeable future. It is a drug with proven benefits and a lower risk of bleeding than prasugrel. The availability of generic clopidogrel in cost-conscious times is also going to encourage its use. High inter-patient variability reduces the effectiveness of clopidogrel in some, but this may be partially offset by using the higher loading dose as per CURRENT-OASIS may be a regimen that is used by some centres to try to reduce these issues. Prasugrel may have an advantage over clopidogrel in some circumstances because of its faster antiplatelet action and less variable response, but this must be weighed against the increased risk of bleeding, which can be fatal. Finally there is a new oral reversible antiplatelet agent, ticagrelor, on the horizon, which may overshadow both clopidogrel and prasugrel. As yet it is still being investigated, but recent results from the PLATO study  comparing it to clopidogrel found no increase in the rate of bleeding and an increase in the numbers of lives saved. Once ticagrelor becomes available we may find that it will replace clopidogrel and prasugrel. In the meantime clopidogrel is going to remain first line. Despite its additional cost, prasugrel does have a place in therapy, for those carefully selected patients at high risk of thrombus but who are at a lower risk of bleeding.
184.108.40.206.219/pctsla/mtrac/productinfo/verdicts/C/ClopidogrelACS.pdf (Accessed March 23 2010).
2. KH Mak, G Belli, et al. J Am Coll Cardiol 1996;27:494–503.
3. CURE study Investigators. Eur Heart J 2000;21(24):2033–41.
4. M Bertrand, HJ Rupprecht, et al. The Clopidogrel aspirin stent international cooperative study (CLASSICS) 2000;102:624–29.
5.emc.medicines.org.uk/medicine/9483/SPC/Plavix+(sanofi-aventis)/ (accessed 23 March 2010).
6.emc.medicines.org.uk/medicine/21504/SPC/Efient+5mg+%26+10mg+film-ed+tablets+(Eli+Lilly+and+Company+Ltd+Daiichi+Sankyo+UK+Limited)/ (Accessed 23 March 2010).
7. National Institute for Health and Clinical Excellence. October 2009.
8. MH Koo, JJ Nawarskas, et al. Cardiol Rev 2008;16:314–18.
9. CURE trial investigators. N Engl J Med 2001;345:494–502.
10. NICE. July 2004.
11. Chau D, Lo C, et al. N Engl J Med 2005;352:1179–89.
12. The COMITT collaboration group. Lancet 2005;366:1607–21.
13. www.theheart.org/article.995967.do (accessed 12 March 2010).
14. Wiviott SD et al. N Engl J Med 2007;357:2001–15.
15. Wiviott SD et al. Circulation 2008;118:1626–36.
16. Montalescot G, Wiviott S, et al. Lancet 2009;373:723–31.
17. MINAP. How the NHS manages heart attacks. Eighth Public report. 2009 Prepared on behalf of the MINAP Steering Group. July 2009. Available at www.rcplondon.ac.uk/clinical-standards/organisation/partnership/Documents/minap_public_report_2009.pdf
18. Task Force for Diagnosis and Treatment of Non ST-Elevation Myocardial Infarction Acute Coronary Syndrome of the European society of Cardiology. Eur Heart J 2007;1598–1660.
19. Laine, L, Hennekens C. Am J Gastroenterology 2010;105:34–41.
20.www.ema.europa.eu/humandocs/PDFs/EPAR/Plavix/32895609en.pdf (accessed 22 March 2010).
21.www.nelm.nhs.uk/en/NeLM-Area/Evidence/Patient-Safety/Drug-Safety-Update-Interaction-between-clopidogrel-and-proton-pump-inhibitors/?query=ppi clopidogrel&rank=60 (Accessed 22 March 2010).
22. Patel A, Jones S, et al. Br J Cardiol 2009;16:281–6.
23. JRCALC guidelines. Clopidogrel. Available at www2.warwick.ac.uk/fac/med/research/hsri/emergencycare/prehospitalcare/jrcalcstakeholderwebsite/ (accessed 22 March 2010).
24. http://www.theheart.org/article/995621.do (Accessed March 23 2010)